CellCept Beats Azathioprine in Lupus Nephritis

Action Points

Explain that maintenance therapy with the immunosuppressive agent mycophenolate mofetil (CellCept) was superior to azathioprine in preventing treatment failure among patients with lupus nephritis.

Point out that patients receiving mycophenolate also were less likely to experience a renal flare.

Maintenance therapy with the immunosuppressive agent mycophenolate mofetil (CellCept) was superior to azathioprine in preventing renal relapse among patients with lupus, an international phase III trial showed.

Compared with patients randomized to azathioprine, those receiving mycophenolate mofetil had a hazard ratio for treatment failure of 0.44 (95% CI 0.25 to 0.77, P=0.003), according to Mary Anne Dooley, MD, of the University of North Carolina in Chapel Hill, and colleagues.

Patients receiving mycophenolate also were less likely to experience a renal flare (HR 0.50, 95% CI 0.26 to 0.93, P=0.03), the researchers reported in the Nov. 17 New England Journal of Medicine.

Despite overall improvements in the treatment of systemic lupus erythematosus, nephritis remains a major source of morbidity and mortality, and therapies such as intravenous cyclophosphamide -- long the standard of care -- can be highly toxic.

Other agents that have been used for induction and remission include glucocorticoids and azathioprine, but these drugs also are associated with long-term toxicities and limited efficacy.

Because small studies have suggested that mycophenolate mofetil might be beneficial, Dooley and colleagues conducted a double-blind randomized study that included 227 patients.

Participants had active lupus nephritis at baseline, and those that responded to 24 weeks of induction therapy with oral mycophenolate or intravenous cyclophosphamide were assigned to receive maintenance therapy with either mycophenolate (1 g twice daily) or azathioprine (2 mg/kg/day).

They also could receive up to 10 mg of prednisone each day.

A total of 85% of participants were women.

Fewer than half were white, 10% were black, and one-third were Asian.

Duration of lupus was about five years, and duration of nephritis about three years.

Treatment failure was defined as death, end-stage renal disease, renal flare, doubling of the serum creatinine, or need for additional treatment such as with other immunosuppressive agents.

Rates of treatment failure were 32.4% in the azathioprine group and 16.4% in the mycophenolate mofetil group, while renal failure rates were 23.4% and 12.9%, respectively.

Rescue therapy was needed in 17.1% and 7.8% of the two groups, respectively, and the time to rescue therapy was longer for the mycophenolate group (HR 0.39, 95% CI 0.18 to 0.87, P=0.02), the investigators reported.

On a secondary endpoint that defined treatment failure more broadly to include other events such as an extrarenal lupus flare or study withdrawal, mycophenolate again was superior, with a failure rate of 42.2% compared with 56.8% of the azathioprine group (HR 0.66, 95% CI 0.46 to 0.97, P=0.03).

Efficacy was consistently greater with mycophenolate mofetil regardless of what induction therapy had been given, patient race, or geographic location, although the study was not powered to evaluate differences between patient subgroups.

By the end of the induction phase, only slightly more than 8% of patients in both groups were in complete remission.

However, many patients continued to improve throughout the 36 months of the continuation phase, with 62.1% and 59.5% of those in the mycophenolate mofetil and azathioprine groups, respectively, eventually achieving complete remission.

"This finding suggests that the distinction between induction therapy and maintenance therapy in patients with lupus nephritis may be an artificial one," the investigators observed.

Almost all patients experienced adverse events, with the most common being infections.

Serious infections occurred in only about 10% of patients in each group, but fewer withdrawals for adverse events occurred in the mycophenolate mofetil group (25.2% versus 39.6%, P=0.02).

Another difference in adverse events was that leukopenia was significantly more common in the azathioprine group (P=0.06).

One patient in the azathioprine group died following a car accident and one in that group developed uterine carcinoma in situ.

Limitations of the study included the fact that serial kidney biopsies were uncommon, and long-term outcomes and complications remain unknown.

In addition, few black patients were included because the majority did not meet the response criteria during the induction phase.

The duration of treatment with mycophenolate also has not been determined.

"Hence, improved biomarkers of response are needed to distinguish disease remission from remission that occurs while the patient is receiving treatment," Dooley and colleagues wrote.

In an accompanying editorial, Frédéric A. Houssiau, MD, PhD, of Université catholique de Louvain in Brussels, noted that another study comparing these two drugs for maintenance in lupus nephritis found no differences in flare rates.

A possible explanation for the divergent findings, according to Houssiau, was that the earlier trial was conducted in a less diverse, mostly white, European population.

"Taken together, both studies provide good news: two drugs that have a reasonably good toxicity profile ... can be proposed as long-term treatment, keeping in mind that not all patients respond to or tolerate either agent and that some conditions contraindicate their use (e.g., mycophenolate should be avoided during pregnancy, and azathioprine cannot be prescribed to persons with thiopurine methyltransferase deficiency)," he stated.

The study was funded by Vifor Pharma, which was formerly Aspreva Pharmaceuticals.

The investigators disclosed receiving grants and acting as consultants for multiple companies, including Vifor, Roche, Teva, Genentech, Centocor, GlaxoSmithKline, Novartis, and Wyeth. Two investigators were employees of Vifor.

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